Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

Priya S Kishnani; Patricia I Dickson; Laurie Muldowney; Jessica J Lee; Amy Rosenberg; Rekha Abichandani; Jeffrey A Bluestone; Barbara K Burton; Maureen Dewey; Alexandra Freitas; Derek Gavin; Donna Griebel; Melissa Hogan; Stephen Holland; Pranoot Tanpaiboon; Laurence A Turka; Jeanine J Utz; Yow-Ming Wang; Chester B Whitley; Zoheb B Kazi; Anne R Pariser

doi:10.1016/j.ymgme.2015.11.001

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

Mol Genet Metab. 2016 Feb;117(2):66-83. doi: 10.1016/j.ymgme.2015.11.001. Epub 2015 Nov 10.

Authors

Priya S Kishnani¹, Patricia I Dickson², Laurie Muldowney³, Jessica J Lee⁴, Amy Rosenberg⁵, Rekha Abichandani⁶, Jeffrey A Bluestone⁷, Barbara K Burton⁸, Maureen Dewey⁹, Alexandra Freitas¹⁰, Derek Gavin¹¹, Donna Griebel¹², Melissa Hogan¹³, Stephen Holland¹⁴, Pranoot Tanpaiboon¹⁵, Laurence A Turka¹⁶, Jeanine J Utz¹⁷, Yow-Ming Wang¹⁸, Chester B Whitley¹⁹, Zoheb B Kazi²⁰, Anne R Pariser²¹

Affiliations

¹ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: priya.kishnani@duke.edu.
² Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90505-2006, USA. Electronic address: pdickson@labiomed.org.
³ Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: laurie.muldowney@fda.hhs.gov.
⁴ Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: jessica.j.lee@fda.hhs.gov.
⁵ Division of Therapeutic Proteins, Office of Biotechnology Products, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: amy.rosenberg@fda.hhs.gov.
⁶ Shire, Lexington, MA 02421, USA. Electronic address: rabichan@shire.com.
⁷ Diabetes Center, University of California, San Francisco, San Francisco, CA 94143-0540, USA. Electronic address: jeff.bluestone@ucsf.edu.
⁸ Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital, Chicago, IL 60611, USA. Electronic address: bburton@luriechildrens.org.
⁹ Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: maureen.dewey@fda.hhs.gov.
¹⁰ National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: afreitas@rarediseases.org.
¹¹ National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: dgavin@rarediseases.org.
¹² Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: donna.griebel@fda.hhs.gov.
¹³ Saving Case & Friends, Inc., a Hunter Syndrome Research Foundation, Thompson's Station, TN 37179, USA. Electronic address: melissa@savingcase.com.
¹⁴ National MPS Society, Durham, NC 27709, USA. Electronic address: steve.holland@thomsonreuters.com.
¹⁵ Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ptanpaib@childrensnational.org.
¹⁶ Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: lturka@partners.org.
¹⁷ University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: utz002@umn.edu.
¹⁸ Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: yowming.wang@fda.hhs.gov.
¹⁹ University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: whitley@umn.edu.
²⁰ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: zoheb.kazi@dm.duke.edu.
²¹ OTS, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: anne.pariser@fda.hhs.gov.

PMID: 26597321
DOI: 10.1016/j.ymgme.2015.11.001

Abstract

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

Keywords: Enzyme replacement therapy; Immune tolerance; Inborn errors of metabolism; Lysosomal storage diseases; Neutralizing antibodies; Orphan drugs; Rare diseases.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Enzyme Replacement Therapy
Humans
Hydrolases / immunology
Hydrolases / therapeutic use*
Immune Tolerance
Lysosomal Storage Diseases / drug therapy*
Lysosomal Storage Diseases / immunology
Recombinant Proteins / immunology
Recombinant Proteins / therapeutic use

Substances

Recombinant Proteins
Hydrolases